Farnesoid X receptor agonist for the treatment of chronic hepatitis B: A safety study

Robin Erken, Patrice Andre, Elise Roy, Neeltje Kootstra, Noelie Barzic, Hugo Girma, Christian Laveille, Pauline Radreau-Pierini, Raphael Darteil, Jacky Vonderscher, Pietro Scalfaro, Pisit Tangkijvanich, Robert Flisiak, Henk Reesink

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20 Citations (Scopus)

Abstract

The nuclear farnesoid X receptor (FXR) regulates bile acid homeostasis and is a drug target for metabolic liver diseases. FXR also plays an important role in hepatitis B virus (HBV) DNA transcription. In vitro and in mice, FXR agonist treatment leads to inhibition of viral replication and a decline in viral proteins, pregenomic RNA (pgRNA) and HBV DNA levels. We aimed to translate this to a clinical use by primarily evaluating the safety and secondary the anti-viral effect of Vonafexor, a FXR agonist, in chronic hepatitis B (CHB) patients. In total, 73 CHB patients were enrolled in a two-part Phase Ib double-blind, placebo-controlled trial. Patients were randomized to receive oral Vonafexor (100, 200 and 400 mg once daily, or 200 mg twice daily), placebo, or entecavir (Part A, n = 48) or to receive Vonafexor (300 mg once daily or 150 mg twice daily), or placebo, combined with pegylated-interferon-α2a (Part B, n = 25) for 29 days. Patients were followed up for 35 days. Enrolled CHB patients were mostly HBeAg-negative. Vonafexor was overall well tolerated and safe. The most frequent adverse events were moderate gastrointestinal events. Pruritus was more frequent with twice-daily compared with once-daily regimens (56%–67% vs. 16%, respectively, p < 0.05). Vonafexor monotherapy of 400 mg once daily decreased HBsAg concentrations (–0.1 log 10 IU/mL, p < 0.05), and Vonafexor/pegylated-IFN-α2a combination therapy decreased HBcrAg and pgRNA. In conclusion, Vonafexor was safe with a decline in HBV markers observed in CHB patients suggesting a potential anti-viral effect the therapeutic potential of which has to be evaluated in larger trials.

Original languageEnglish
Pages (from-to)1690-1698
Number of pages9
JournalJournal of viral hepatitis
Volume28
Issue number12
Early online date2021
DOIs
Publication statusPublished - Dec 2021

Keywords

  • HBV therapy
  • Vonafexor
  • cccDNA transcription
  • farnesoid X receptor
  • phase Ib

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